Dementia or memory loss is the hallmark symptom of Alzheimer’s disease (AD). The exploration of AD helps to identify the problems involved in neural structures such as the default network and role of genetic factors. Episodic memory (EM) directly deals with the memory system that allows an individual to consciously retrieve an old experience or an episode of life. EM plays an important role in AD. The World Health Organization predicts that, by 2025, about 75% of the estimated 1.2 billion people aged 60 years and older will reside in developing countries. It is estimated that the number of people living with dementia will almost double every 20 years to 42.3 million in 2020 and 81.1 million in 2040. In India, there are lesser number of good quality scientific studies/researches that deal with the real trend of the disease and determine the mechanism involved, risk factors, investigations on dementia, decline in awareness, and inadequate availability of social benefit. India is a country with varied cultures, and, therefore, conducting a genetic epidemiological study here has greater advantage. The goal of this review is to provide knowledge and increase the awareness of dementia associated with AD, as well as to understand the mechanism involved and its treatment, which can be useful for researchers or scientists in the near future.

Nervous system is divided into two parts, that is, the central nervous system (CNS) and peripheral nervous system (PNS). The CNS is composed of the brain and spinal cord, whereas the PNS is composed of the spinal nerves that branch from the brain.[1] The cerebrum is the largest part of the brain, and it is made up of the right hemisphere and left hemisphere. It has many functions such as vision, hearing, learning, emotions, and fine control movement.[2] The brainstem includes the midbrain (mesencephalon), which is a relatively narrow band of the brainstem surrounding the cerebral aqueduct. Pons (metencephalon) is located below the cerebellum, its ventral bulge it means pons is clearly visible, and the medulla oblongata (myelencephalon) extends from the inferior pontine sulcus to the spinal cord. It mostly performs automatic functions such as breathing, heart rate control, body temperature regulation, sneezing, and coughing.[3] The brain is made up of two types of cells, that is, the nerve cells and glial cells. The nerve cells consist of a cell body, axons, and dendrites and play a specific role when conveying message or information through chemical and electrical signals. Glial (Greek word meaning glue) cells are the cells of the brain that provide the neurons with nourishment, protection, and structural support.[1]

Memory

Memory is an important function of the brain and is the ability of an individual to record information, retain and recall them whenever needed, and, moreover, the use this information to adapt one’s responses to the environment; hence, it is vital for survival.[4] It is also defined as the special facility of the brain that retains the events developed during the process of learning and mediated by the nervous system. Learning is defined as the ability to alter behavior on the basis of experience.[5]

Memory is the ability of an individual to record sensory stimuli, events, information, etc. Learning is the process of acquiring knowledge about the world, whereas memory could be considered as the retention of the acquired knowledge.[6] Memory refers to the persistence of learning that can be revealed at a later time, whereas learning is defined as the process of acquiring new information or skills. Memory is the usual consequence of learning and reflects the enduring changes in the nervous system that result from transient experiences.[7] Memory loss, also called amnesia, happens when a person loses the ability to remember information and events they would normally be able to recall. Memory loss due to the dysfunction of the episodic memory (EM) system generally follows a pattern known as Ribot’s law, which states that events just prior to an ictus are most vulnerable to decay, whereas remote memories are more resistant.[8] The memory system and its anatomical structures are given in [Table 1].

Dementia is defined as an acquired deterioration in cognitive abilities that impair the successful performance of activities of daily living. Neuropsychiatric and social deficits also develop in many dementia syndromes resulting in depression, withdrawal, hallucinations, delusions, agitation, insomnia, and disinhibition.[9] Dementia is a mental disorder characterized by the loss of intellectual ability, which is sufficiently severe to interfere with one’s social and occupational activity.[10] Dementia is characterized by the presence of memory impairment in the presence of other cognitive defects. The different types of dementia are listed in [Table 2].[11],[12],[13],[14]

Amnesia also known as amnesic syndrome is a deficit in memory caused by brain damage, disease, or psychological trauma. Essentially, amnesia is loss in memory. The memory can be either wholly or partially lost due to the extent of damage that was caused, and that damage is associated with damage to the medial temporal lobe.[15] There are two main types of amnesia: retrograde amnesia and anterograde amnesia.

Retrograde amnesia

Retrograde amnesia is the inability to retrieve information that was acquired before a particular date, usually the date of an accident or operation. Retrograde memory loss almost always occurs in association with anterograde amnesia, which is characterized by an inability to learn new information.[16]

Anterograde amnesia

Anterograde amnesia is the inability to transfer new information from the short-term store to the long-term store.[17]

Aphasia

The neural substrate of language is composed of a distributed network centered in the perisylvian region of the left hemisphere. The posterior pole of this network is located at the temporoparietal junction and includes a region known as Wernicke’s area. An essential function of Wernicke’s area is to transform sensory inputs into their lexical representations so that these can establish the distributed associations that give the word its meaning. The anterior pole of the language network is located in the inferior frontal gyrus and includes the region called as Broca’s area. Wernicke’s and Broca’s areas are interconnected with each other and with additional perisylvian, temporal, prefrontal, and posterior parietal regions making up a neural network subserving the various aspects of language function. Damage to any one of these components, because their interconnections can give rise to language disturbances, is called as aphasia.[18] Different types of aphasia are Wernicke’s aphasia, Broca’s aphasia, global aphasia, conduction aphasia, isolation aphasia, and anomic aphasia, as listed in [Table 3].[19],[20],[21]

There is an acute or severely impaired fluency, which cannot be accounted for by corticobulbar, cerebellar, or extrapyramidal dysfunction. Writing, reading, and comprehensions are intact; therefore, this is not a true aphasic syndrome.[22]

Signs and symptoms

Memory impairment is the hallmark symptom of Alzheimer’s disease (AD) and usually involves behaviors such as forgotten appointments, straying away from home, misplaced items, and repetitive questions. Along with memory problems, AD can be recognized by insomnia, anxiety, depression, disruptive behavior, and hallucinations. Several studies have found evidence that AD is a disease that is caused by or is a result of decreased metabolic activity in the brain.[23][Figure 1] shows the difference between the brain from a healthy patient and the brain from a patient with AD. The deposition of protein amyloid (brain) is noticed in different forms of AD. It is composed of a secreted peptide (Aβ) that can be either 40 or 42 amino acids long (Aβ 1–40 or Aβ 1–42). Aβ 1–42 forms insoluble amyloid fibrils and is deposited early and selectively in the senile plaques that are a pathological hallmark of AD.[24]

Figure 1: The difference between the brain of a healthy patient and the brain of a patient with Alzheimer’s brain

Stage three generally lasts for 1–3 years with risk factors that include age, head injury, and most often also involving incontinence, swallowing difficulty, the development of skin infections, and seizures.[25]

Causes

Normal aging can cause some forgetfulness. It is normal to have some trouble learning new material or needing more time to remember it. However, normal aging does not lead to dramatic memory loss. Such memory loss is due to other diseases.[26] Many areas of the brain help create and retrieve memories. A problem in any of these areas can lead to memory loss. Memory loss may result from a new injury to the brain, which is caused by or is present after the following:

Epilepsy that is not well controlled. Illness that results in the loss of or damage to brain tissue or nerve cells such as Parkinson’s disease (PD), Huntington’s disease (HD), or multiple sclerosis.

Low levels of important nutrients or vitamins such as low Vitamin B12.

Epidemiology

Worldwide, an estimated 35.6 million people were living with dementia in 2010. This number is estimated to nearly double every 20 years, to 65.7 million in 2030 and 115.4 million in 2050.[30] Census reports indicate that the Indian population has approximately tripled during the last 50 years, but the number of elderly Indians has increased more than fourfold. When considering the continuation of the trend, the United Nation predicts that the Indian population will again grow by 50% in the next 50 years.[31] Epidemiological studies found a significant correlation between the dietary intake of vegetables and improvement in cognitive function in the elderly. For instance, aging women consuming cruciferous vegetables (e.g., broccoli and cauliflower) showed less cognitive decline than those not consuming them.[32] Several meta-analyses have resulted in roughly similar estimates of dementia prevalence across regions. The estimated global dementia prevalence in people aged over 60 is approximately 3.9%, with the regional prevalence being 1.6% in Africa, 3.9% in Eastern Europe, 4.0% in China, 4.6% in Latin America, 5.4% in Western Europe, and 6.4% in North America.[33] The global annual incidence of dementia is estimated to be around 7.5 per 1000 population.[34] The United Nations estimated that the number of people suffering from age-related neurodegeneration, particularly from AD, will exponentially increase from 25.5 million in 2000 to an estimated 114 million in 2050.[35] Several meta-analyses have resulted in roughly similar estimates of dementia prevalence across regions. The estimated global dementia prevalence in people aged over 60 is approximately 3.9%, with the regional prevalence being 1.6% in Africa, 3.9% in Eastern Europe, 4.0% in China, 4.6% in Latin America, and 5.4% in Western. The incidence rate of dementia increases exponentially with age, and incidence rates across regions of dementia are quite similar.[33]

Hence, the global trend in the phenomenon of population aging has dramatic consequences for public health, healthcare financing, and delivery systems in the world and, especially, in developing countries.[36]

Evaluation of Memory Impairment

Physical and neurological examination

A thorough general and neurological examination is essential to document the presence of dementia, look for other signs of nervous system involvement, and search for clues suggesting a systematic disease that might be responsible for cognitive disorders. The examination considers the following aspects:

AD does not affect the motor system until later in the course; in contrast, patients with frontotemporal dementia (FTD) often develop axial rigidity, supranuclear gaze palsy, or features of amyotrophic lateral sclerosis.

Dementia with Lewy bodies (DLBs) may have initial symptoms such as the new onset of a Parkinsonism More Details syndrome (resting, tremor, bradykinesia, and festinating gait) with dementia.

Creutzfeldt–Jakob disease (CJD) is suggested by the presence of diffuse rigidity, a kinetic state, and myoclonus.[9]

Several neurological features which affect the dementia, cognition and AD, i.e., extrapyramidal, bradykinesia, rigidity, tremor, chorea and these are associated with the PD, CBD, PSP, FTP, DLBs, VD, HD.[37]

Cognitive and neuropsychiatric examination

Brief screening tools such as the mini-mental state examination (MMSE) help to confirm the presence of cognitive impairment and to follow the progression of dementia.

The MMSE, an easily administered 30-point test of cognitive function, contains a test of orientation, working memory, language comprehension, naming, and copying.

In FTD, the earliest deficit often involves frontal executive or language function.

Patients with DLB have more severe deficits in visuospatial function but perform better on EM tasks than patients with AD.

In delirium, deficits tend to fall in the area of attention, working memory, and frontal function.[38]

Clinical manifestation

The cognitive changes with AD tend to follow a characteristic pattern, beginning with memory impairment and spreading to language and visuospatial deficits.

However, 20% of patients with AD present with nonmemory complaints such as word finding, organizational, and navigational difficulties.

Delusions are common and usually simple in quality such as delusions of theft, infidelity, or misidentification.[39]

Pathophysiological Discussion of Synapses Where Memory is Stored

Synaptic plasticity refers to the changes in the strength of synaptic function, and this process is currently a major focus of research on the neurobiology of learning and memory.[39] Synaptic plasticity includes both short-term changes in the strength or efficacy of neurotransmission as well as longer-term changes in the structure and number of synapses.[40]

The experimental models of changes in synaptic strength or effectiveness in response to repeated electrical stimulation are thought to mimic physiologic plasticity. These changes are referred to as long-term potentiation (LTP) when synaptic strength increases or long-term depression (LTD) when it decreases. These modifications in synaptic strength, both positive and negative, distributed across thousands to millions of connections among neurons, are believed to form the physical and biochemical substrate for memory and learning.[41] Short-term memory, generally, does not require protein synthesis but results from changes in synaptic strength within synapses, whereas in the case of long-term memory, storage, generally, requires the transcription and translation of a new protein that enhances the strength or number of active synapses.[42]

Signaling Pathway of Learning and Memory System

Multiple synaptic signal transduction pathways contribute to the reinforcement of a memory by multiple sensory stimuli, for example, sound, sight, and taste. The following three types of neurotransmitter receptors are shown: inotropic receptors that open ion channels (e.g., the N-methyl-d-aspartate receptor (NMDA) and α-amino-3-hydroxy-5-methyl-4-ioxazolepropionic acid (AMPA)-type glutamate receptors shown at top left), metabotropic receptors (e.g., for glutamate, acetylcholine, and serotonin at upper right) linked to synthesis of inositol phosphates and stimulation of protein kinase C (PKC), and transmembrane receptors linked to the generation of cyclic adenosine monophosphate (cAMP), shown at upper far right. Most long-term memories require gene transcription and translation of new protein, whereas short-term memories can result from local synaptic changes, for example, phosphorylation and/or addition of AMPA-type glutamate receptors shown at the upper left. Cross-talk among the pathways contributes to synergism among stimuli and also provides redundancy if one pathway is affected by genetic or acquired disorders.[43] Memory loss is associated with brain shrinkage and localized loss of neurons, mainly in the hippocampus and basal forebrain. The loss of cholinergic neurons in the hippocampus and frontal cortex is a feature of the disease and is thought to underlie the cognitive deficit and loss of short-term memory that occur in AD. The main pathological features of memory loss and AD comprise amyloid plaques (APs), neurofibrillary tangles, and a loss of neurons (particularly the cholinergic neurons of the basal forebrain). The AD neuropathologic change is now ranked on three parameters (Amyloid, Braak, CERAD) to obtain an “ABC” score: histopathologic assessments of beta-amyloid (Aβ)-containing amyloid plaques (A), Braak staging of neurofibrillary tangles (B), and scoring of neuritic amyloid plaques (C). AP consists of aggregates of the A fragment of amyloid precursor protein, a normal neuronal membrane protein, produced by the action of the alpha and beta secretease. AD-associated excessive A formation results in neurotoxicity.[44]

Acetylcholine is the most important neurotransmitter involved in the regulation of neurotransmission of cognitive impairment or its functions. Cholinergic transmission is terminated by acetylcholine hydrolysis through the enzyme acetylcholinesterase (AChE), which is responsible for the degradation of acetylcholine to acetate and choiline in the synaptic cleft. According to the cholinergic hypothesis, memory impairment in a patient with senile dementia is due to selective and irreversible deficiency in the cholinergic functions in the brain.[45] A number of neurotransmitter receptors and growth factors appear to influence the synaptic plasticity and memory through these molecular pathways.[46] The NMDA-type glutamate receptor has been shown to be important in hippocampal LTP because of its role as a coincidence detector that opens its channel when pre- and postsynaptic neurons fire together.[47] The large amount of calcium entering through its channel activates CaMKII via phosphorylation, which in turn phosphorylates AMPA receptors and increases their number in the postsynaptic membrane. A change in the number and activity of AMPA receptors in synapses is thought to be an important mechanism for the up- or downregulation of synaptic function in LTP or LTD. Several other neurotransmitter receptors including metabotropic glutamate, muscarinic cholinergic, serotonin, dopamine, and adrenergic receptors are coupled to Mitogen-activated protein kinase (MAPK) activation through protein kinase A (PKA) or PKC. Linkages between these receptor pathways and the MAPK cascade and transcriptional activation may be responsible for the effects of commonly prescribed drugs on cognition.[46] For example, anticholinergic or glutamate-blocking drugs can impair memory, whereas stimulants or antidepressants that enhance the effects of serotonin, dopamine, or norepinephrine can enhance cognition. Growth factors such as Brain-derived neurotrophic factor (BDNF) and nerve growth factor, acting through receptor tyrosine kinase receptors, also stimulate synaptic plasticity through several mechanisms, including the activation of the MAPK cascade.[48]

General Mechanism of Memory Impairment

This impairment of memory is correlated with the loss of basal forebrain cholinergic neurons. The role of these neurons in learning and memory is well known, and its pharmacological blockage leads to the impairment of learning and memory. Scopolamine-induced amnesic animal models are used to screen for agents that are claimed to have cognition-enhancing activity through the stimulation of the cholinergic system, thus making them candidates for the treatment of AD.[49] Geriatric diseases refer to cerebral or spinal disorders caused by abnormal neuronal death and are accompanied by impaired cognitive, walking, and motor abilities. The lack of acetylcholine due to the reduction of hippocampal cholinergic neuronal activity is one of the most important causes of memory impairment. Further, although there are many choline acetyl transferase agonists and AChE inhibitors for memory enhancement, they are ineffective and controversial due to their serious side effects and toxicity. For this reason, research has tried to identify memory enhancers from natural materials. Scopolamine is a muscarinic receptor antagonist that is frequently used in memory-impaired animals. It inhibits connections between acetylcholine and muscarinic receptors, thereby temporarily blocking information transmission and causing learning and memory impairment.[50]

Drug Delivery, Targeting, and the Blood–Brain Barrier

For the desired CNS effect to be achieved, a systematically administered compound must pass through the capillary endothelium of the blood–brain barrier (BBB). Invasive strategies may circumvent the BBB through neurosurgical approaches to implant cells, tissues, or drug delivery systems. Pharmacologically based strategies are being developed to deliver drugs, polymers, or liposomes to their CNS targets, and innovative physiologic-based approaches make use of the intrinsic pathway of the carrier-mediated transport of nutrients (for example, levodopa via the neutral amino acid transport system) or receptor-mediated transport of peptides, for example, insulin and transferring.[51]

Medications

Allopathic medication for the treatment of memory impairment.

Types of drugs: The U.S. Food and Drug Administration has approved the following two types of medications: cholinesterase inhibitors (Aricept, Exelon, Razadyne, and Cognex) and memantine (Namenda)—to treat the cognitive symptoms (memory loss, confusion, and problems with thinking and reasoning) of AD. The treatment of memory loss is illustrated in [Table 4].[52]

Docosahexaenoic acid (DHA): DHA is a major omega-3 fatty acid of the brain that is necessary for good brain function. The brains of 42 modern mammalian species were studied, and they were found to be similar in brain chemistry, particularly in the predominant use of DHA in the membrane-rich neural tissues at synapses and in the retina. It is found mainly in oily fish. DHA is particularly important for mental performance and has an important role in the development of the brain during fetal development and infancy. It is, therefore, essential that pregnant women either have a regular dietary source of these omega-3 fats or supplement them.[64]

Pyroglutamate: N-terminal-truncated Aβ derivatives, especially the forms having pyroglutamate at the 3rd position (AβpE3) or at the 11th position (AβpE11), have become the topic of considerable study. The master of communication that has a key brain chemical in enhancing memory and mental function is the amino acid pyroglutamate and its derivatives, which are highly concentrated in the human brain and spinal fluid. It improves learning, memory, concentration, and the speed of reflexes.[65]

Conclusion

Healthcare awareness contributes significantly to the longer and stress-free lives of people. A complete knowledge about noncommunicable diseases including dementia plays an important role in prolonging the life of human beings. Prevalence indicates that the number of people with dementia will continue to grow, particularly among the elderly. Such investigations in India could better signal the true state of dementia burden, help plan for future healthcare needs, and also offer neurobiological problems that impact fundamental lifestyle and environmental risk factors/protective factors for AD. Researchers continue to search for different ways to treat AD and dementias. Currently, there are many therapies and pharmacologic treatments that directly concentrate to stop the brain cell death associated with AD.